Thromb Haemost 1998; 80(01): 10-23
DOI: 10.1055/s-0037-1615131
Review Articles
Schattauer GmbH

Heparin and Cancer

Leo R. Zacharski
1   From the VA Medical and Regional Office Center, White River Junction, Vermont; and the Department of Medicine, Dartmouth Medical School, Hanover, New Hampshire, USA
,
Deborah L. Ornstein
1   From the VA Medical and Regional Office Center, White River Junction, Vermont; and the Department of Medicine, Dartmouth Medical School, Hanover, New Hampshire, USA
› Author Affiliations
Further Information

Publication History

Received 03 December 1997

Accepted after resubmission 23 March 1998

Publication Date:
08 December 2017 (online)

Summary

Heparin has been the subject of intensive investigation for decades by both basic and clinical scientists because of its usefulness as a therapeutic anticoagulant (1). In addition to its effects on coagulation, however, heparin exhibits many other activities which seem to have little to do with anticoagulation (2). Goerner first observed an effect on the natural history of malignancy in 1930 when he demonstrated that heparin inhibited tumor growth in experimental animals (3). A substantial body of literature on heparin and cancer has developed during the ensuing decades. A recent increase in interest has resulted from observations made during prospective, randomized clinical trials which compared unfractionated heparin (UH) with low molecular weight heparin (LMWH) for the prevention and treatment of venous thromboembolism (VTE). Several studies have shown improvement in short to intermediate term survival in the subset of patients with cancer who received LMWH. This improved outcome has been emphasized in two published meta-analyses (4, 5), and the trend is supported by the results of a more recent prospective study (6). The improved cancer outcome could not be attributed to prevention of VTE in any of the studies; therefore, it is reasonable to hypothesize that a beneficial effect of heparin may be mediated by mechanisms independent of anticoagulation.

Heparin has several properties that may plausibly explain its effect on experimental and human malignancy. The purpose of this paper is to summarize the literature on heparin and cancer and review mechanisms by which heparin may exert antineoplastic activity. The goal is to encourage both definitive clinical trials of heparin on cancer outcome and further studies of drug mechanisms in human malignancy. LMWH, with its favorable pharmacokinetic attributes, is suitable for chronic outpatient administration and is an excellent candidate for further investigation. Such a departure from conventional experimental cytotoxic chemotherapy holds promise for development of novel forms of growth regulatory therapy that interrupt pathways of cancer progression. In this review, “heparin” will refer to unfractionated heparin (UH), and “UH” and “LMWH” will be used to distinguish between the two molecular forms.

 
  • References

  • 1 Hirsh J. Heparin.. N Engl J Med 1991; 324: 1565-74.
  • 2 Ruoslahti E, Yamaguchi Y. Proteoglycans as modulators of growth factor activities.. Cell 1991; 64: 867-9.
  • 3 Goerner A. The influence of anticlotting agents on transplantation and growth of tumor tissue.. J Lab Clin Med 1930; 16: 369-72.
  • 4 Lensing AWA, Prins MH, Davidson BL, Hirsh J. Treatment of deep venous thrombosis with low-molecular weight heparins. A meta-analysis.. Arch Int Med 1995; 155: 601-7.
  • 5 Siragusa S, Cosmi B, Piovella F, Hirsh J, Ginsburg JS. Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: results of a meta-analysis.. Am J Med 1996; 100: 269-77.
  • 6 von Tempelhoff G F, Dietrich M, Neimann F, Schneider D, Hommel G, Heilmann L. Blood coagulation and thrombosis in patients with ovarian malignancy.. Thromb Haemost 1997; 77: 456-61.
  • 7 Wood Jr S, Holyoke ED, Yardley JH. An experimental study of the influence of adrenal steroids, growth hormone, and anticoagulants on pulmonary metastasis formation in mice.. Proc Amer Assoc Cancer Res 1956; 2: 157-8.
  • 8 Lawrence EA, Bowman DE, Moore DB, Bernstein GI. A thromboplastic property of neoplasms.. Surg Forum 1952; 3: 394-8.
  • 9 Lawrence EA, Moore DB, Bernstein GI. The ability of the pulmonary vascular system to influence the spread of tumor emboli.. J Thoracic Surg 1953; 26: 233-40.
  • 10 Terranova T, Chiossone F. The coagulation factor in the attachment of neoplastic cells introduced into the blood stream.. Boll Soc Ital Biol Sper 1952; 28: 1224-5.
  • 11 Kudrjaskov BA, Kalishevskaya TM, Kolomina SM. Blood anticoagulating system and malignant tumours.. Nature 1969; 222: 548-50.
  • 12 Fisher B. Experimental studies of factors which influence hepatic metastases. VIII. Effects of anticoagulants.. Surgery 1961; 50: 240-7.
  • 13 Agostino D, Cliffton EE. Anticoagulants and the development of pulmonary metastases.. Arch Surg 1962; 84: 449-53.
  • 14 Ivarsson L, Rudenstam C-M. Heparin, dextran 1000 and metastasis formation after IV tumour cell injection in dextran non-sensitive rats.. Brit J Cancer 1975; 32: 502-8.
  • 15 Owen Jr. CA. Anticoagulant treatment of rats with Walker 256 carcinosarcomas.. J Cancer Res Clin Oncol 1982; 104: 191-3.
  • 16 Drago JR, Weed P, Fralisch A. The evaluation of heparin in control of metastasis of Nb rat androgen-insensitive prostate carcinoma.. Anticancer Res 1984; 4: 171-2.
  • 17 Shaeffer Jr. Interference in localization of I131 fibrinogen in rat tumors by anticoagulants.. Am J Physiol 1964; 206: 573-9.
  • 18 Heyes H, Kohle W. Heparin-dependent inhibition of microangiopathic haemolytic anemia in an experimental rat tumor.. Thromb Haemost 1979; 42: 140.
  • 19 Koike A. Mechanism of blood-borne metastases. I. Some factors affecting lodgment and growth of tumor cells in the lungs.. Cancer 1964; 17: 450-60.
  • 20 Hilgard P, Beyerle L, Hohage R, Hiemeyer V, Kubler M. The effect of heparin on the initial phase of metastasis formation.. Eur J Cancer 1972; 8: 347-52.
  • 21 van den Brenk HAS, Burch WM, Kelly H, Orton C. Venous diversion trapping and growth of blood-borne cancer cells en route to the lungs.. Brit J Cancer 1975; 31: 46-61.
  • 22 Saba TM, Cho E. Alteration of tumor growth by a purified alpha-2-glyco-protein.. J Reticuloendothelial Soc 1977; 22: 583-96.
  • 23 Csaba G, Korosi J, Horvath C, Mold K, Acs T. Effect of heparin-bound alkylating agents and enzyme inhibitors on neoplastic growth.. Neoplasma 1964; 11: 137-43.
  • 24 Lee AE, Rogers LA, Longcroft JM, Jeffery RE. Reduction of metastasis in a murine mammary tumor model by heparin and polyinosinic-polycytidylic acid.. Clin Exper Metast 1990; 8: 165-71.
  • 25 Sylvester DM, Liu YS, Meadows GG. Augmentation of antimetastatic activity of interferon and tumor necrosis factor by heparin.. Immunopharmacol Immunotoxical 1990; 12: 161-80.
  • 26 Kiricuta I, Todorutiu C, Muresian T, Risca R. Prophylaxis of metastasis formation by unspecific immunologic stimulation associated with heparin therapy.. Cancer 1973; 31: 1392-6.
  • 27 Gorelik E, Bere E, Herberman RB. Mechanisms of the antimetastatic effects of anticoagulant drugs: dependence on natural killer (NK) cell activity.. In: Hemostasis and Cancer.. Muszbek L. ed. CRC Press; Boca Raton, Florida: 1987. pp 37-45.
  • 28 Nagawa H, Paris P, Chauffert B, Martin F. Treatment of experimental liver metastasis in the rat by continuous intraportal infusion of 5-fluorouracil and heparin: a pilot study.. Anticancer Drugs 1990; 1: 149-56.
  • 29 Murata J, Saiki I, Nishimura S, Nishi N, Tokura S, Azuma I. Inhibitory effect of chitin heparinoids on the lung metastasis of B16-BL6 melanoma.. Japanese J Cancer Res: Gann 1989; 80: 866-72.
  • 30 Tsubura E, Yamashita T, Kobayashi M, Higuchi Y. Effect of sulfated polysaccharides on blood-borne pulmonary metastasis in rats.. Gann 1976; 67: 849-56.
  • 31 Kobayashi M, Yamashita T, Tsubura E. Inhibition of blood-borne pulmonary metastasis by sulfated polysaccharides.. Tokushima J Exp Med 1979; 26: 41-51.
  • 32 Vlodavsky I, Mohsen M, Lider O, Svahss CM, Ekre HP, Vigoda M, Ishai-Michaeli R, Peretz T. Inhibition of tumor metastasis by heparanase inhibiting species of heparin.. Invasion and Metastasis 1994; -95 14: 290-302.
  • 33 LaPierre F, Holme K, Lam L, Tressler RJ, Storm N, Wee J, Stack RJ, Castellot J, Tyrrell DJ. Chemical amodifications of heparin that diminish its anticoagulant but preserve its heparanase-hibitory, angiostatic, anti-tumor and anti-metastatic properties.. Glycobiology 1996; 6: 355-66.
  • 34 Hagmar B. Tumour growth and spontaneous metastasis spread in two syngeneic systems.. Acta Path Microbiol Scand 1970; 78: 131-42.
  • 35 van den Brenk HAS, Stone M, Kelly H, Orton C, Sharpington C. Promotion of growth of tumour cells in acutely inflamed tissues.. Brit J Cancer 1974; 30: 246-60.
  • 36 Glaves D, Weiss L. Initial tumor cell arrest in animals of defined coagulative status.. Int J Cancer 1978; 21: 741-6.
  • 37 Antachopoulos CT, Gagos S, Iliopoulos DC, Karayannacos PE, TseleniBalafouta S, Alevras P, Koundouris C, Skalkeas GD. Low-dose heparin treatment does not inhibit SW480 human colon cancer growth and metastasis in vivo.. In Vivo 1996; 10: 527-31.
  • 38 Klener P, Bubenik J, Donner L. Influence of heparin and defibrase on transplantability of syngeneic tumors in mice.. Neoplasma 1978; 25: 631-5.
  • 39 Hagmar B, Norrby K. Evidence for effects of heparin on cell surfaces influencing experimental metastases.. Int J Cancer 1970; 5: 72-84.
  • 40 Hagmar B, Boeryd B. Disseminating effect of heparin on experimental tumour metastases.. Path Europ 1969; 4: 274-82.
  • 41 Lione A, Bosman B. The inhibitory effect of heparin and warfarin treatments on the intravascular survival of B16 melanoma cells in syngeneic C57 mice.. Cell Biol Int Rep 1978; 2: 81-6.
  • 42 Zacharski LR. Basis for selection of anticoagulant drugs for therapeutic trials in human malignancy.. Haemostas 1986; 16: 300-20.
  • 43 Gray BN. Surgical adjuvant therapy for potentially curable cancer: the rationale of adjuvant chemotherapy and anticoagulant therapy.. Aust NZ J Surg 1977; 47: 576-80.
  • 44 Zacharski LR. Rationale for anticoagulant treatment of cancer.. In Hemostatic Mechanisms and Metastasis.. Honn KV, Sloane BF. eds. Martinus Nijhoff; Boston: 1984. pp 368-74.
  • 45 Slichter SJ, Harker LA. Hemostasis and malignancy.. Ann NY Acad Sci 1974; 230: 252-61.
  • 46 Peuscher FW, Cleton FJ, Armstrong L, Stoepman-van Dalen EA, van Mourik JA, van Aken WG. Significance of plasma fibrinopeptide A (FPA) in patients with malignancy.. J Lab Clin Med 1980; 96: 5-14.
  • 47 Rickles FR, Edwards RL, Barb C, Cronlund M. Abnormalities of blood coagulation in patients with cancer: fibrinopeptide A generation and tumor growth.. Cancer 1983; 51: 301-7.
  • 48 Mombellil G, Roux A, Haeberli A, Straub PW. Comparison of 125Ifibrinogen kinetics and fibrinopeptide A in patients with disseminated neoplasias.. Blood 1982; 60: 381-8.
  • 49 Gillis S, Dann EJ, Eldor A. Low molecular weight heparin in the prophylaxis and treatment of disseminated intravascular coagulation in acute promyelocytic leukemia.. Eur J Haematol 1995; 54: 59-60.
  • 50 Sakuragawa N, Hasegawa H, Maki M, Nakagawa M, Nakashima M. Clinical evaluation of low-molecular-weight heparin (FR-860) on disseminated intravascular coagulation (DIC)-a multicenter co-operative double-blind trial in comparison with heparin.. Thrombos Res 1993; 72: 475-500.
  • 51 Kobayashi T, Sasaki T, Ibuka T, Imai K, Monma K, Sakaki N, Tabata I, Ishirvata J, Onozawa Y, Ohno T. Sequential MTX and 5-FU therapy of gastric cancer with systemic bone metastasis and disseminated intravascular coagulation.. Gan To Kagaku Ryoho 1992; 19: 69-74.
  • 52 Coughenour M, Slavik M, Fabian C, Brown N, Cheng CC. Clinical and compatibility studies of 5-fluorouracil (5-FU) and heparin (HN) administered by continuous IV infusion.. Proc Am Assoc Cancer Res. 1988 29. abst 758.
  • 53 Monreal M, Alastrue A, Rull M, Mira X, Muxart J, Rosell R, Abad A. Upper extremity deep venous thrombosis in cancer patients with venous access devices-prophylaxis with low molecular weight heparin (Fragmin).. Thromb Haemost 1996; 75: 251-3.
  • 54 Walsh-McMonagle D, Green D. Low-molecular-weight heparin in the management of Trousseau’s syndrome.. Cancer 1997; 80: 649-55.
  • 55 Albert-Weil J, Nehorais J. A propos de deux cas de neoplasies non justiciable des therapeutiques classiques, traitees per des injections intraveineuses d’heparine et des injections intramusculaires d’un extrait de sang-sue.. Rev Pathol Gen Comparee 1954; 54: 1014-20.
  • 56 Astedt B, Glifberg I, Mattsson W, Trope C. Arrest of growth of ovarian tumor by tranexamic acid.. J Am Med Assn 1977; 238: 154-5.
  • 57 Astedt B, Mattsson W, Trope C. Treatment of advanced breast cancer with chemotherapeutics and inhibition of coagulation and fibrinolysis.. Acta Med Scand 1977; 201: 491-3.
  • 58 Elias EG, Sepulveda F, Mink I. Increasing the efficiency of cancer chemo-therapy with heparin: “Clinical Study”.. J Surg Oncol 1973; 5: 189.
  • 59 Edlis HE, Goudsmit A, Brindley C, Niemetz J. Trial of heparin and cyclophosphamide (NSC-26271) in the treatment of lung cancer.. Cancer Treat Rep 1976; 60: 575-8.
  • 60 Rohwedder JJ, Sagastume E. Heparin and polychemotherapy for treatment of lung cancer.. Cancer Treat Rep 1977; 61: 1399-401.
  • 61 Jamieson GG, Angove RC. Heparinized chemotherapy in the treatment of disseminated lung cancer.. Aust NZ J Med 1979; 9: 381-4.
  • 62 Weber W, Maibach R, Laffer U, Metzger U, Egeli R, Lorenz M, Aeberhard P, Dupont-Lampert V, Nothiger P, Rued T. Early hematological toxicity of adjuvant perioperative intraportal and intravenous chemo-therapy with fluorouracil, mitomycin, and heparin in colorectal cancer.. Anticancer Res 1995; 15: 2197-200.
  • 63 Gondret R, Dominici L, Angelard B, Dubos S, al-Rawi S, Huet Y, Clerque F, Saint-Guily JL. Safety of preoperative enoxaparin in head and neck cancer.. Head Neck 1995; 17: 1-6.
  • 64 Halkin H, Goldberg J, Modan M, Modan B. Reduction of mortality in general medicine in-patients by low-dose heparin prophylaxis.. Ann Int Med 1982; 96: 561-5.
  • 65 Kingston RD, Fielding JWL, Palmer MK. Peri-operative heparin: a possible adjuvant to surgery in colo-rectal cancer?. Int J Colorect Dis 1993; 8: 111-5.
  • 66 Tongren S, Rieger A. The influence of heparin and curable resection on the survival of colon cancer.. Acta Chir Scand 1983; 149: 427-9.
  • 67 Kohanna FH, Sweeney J, Hussey S, Zacharski LR, Salzman EW. Effect of peri-operative low-dose heparin administration on the course of colon cancer.. Surg 1983; 93: 433-8.
  • 68 Kakkar AK, Hedges AR, Williamson RCN, Kakkar VV. Perioperative heparin therapy inhibits late death from metastatic cancer.. Int J Oncol 1995; 6: 885-8.
  • 69 deSoccarraz C, deSoccarraz H. Local treatment of Kaposi’s sarcoma in AIDS patients.. Dermatology 1993; 187: 78.
  • 70 Lebeau B, Chastang C, Brechot J-M, Capron F, Dautzenberg B, Delaisements C, Mornet M, Brun J, Hurdebourcq J-P, Lemarie E. Subcutaneous heparin treatment increases survival in small cell lung cancer.. Cancer 1994; 74: 38-45.
  • 71 Stanford CF. Anticoagulants in the treatment of small cell carcinoma of the bronchus.. Thorax 1979; 34: 113-6.
  • 72 Wereldsma J, Bruggink E, Meijer W, Roukema J, van Putten W. Adjuvant portal liver infusion in colorectal cancer with 5-fluorouracil/heparin versus urokinase versus control.. Cancer 1990; 65: 425-32.
  • 73 Fielding LP, Hittinger R, Grace RH, Fry JS. Randomized controlled trial of adjuvant chemotherapy by portal-vein perfusion after curative resection for colorectal adenocarcinoma.. Lancet 1992; 340: 502-6.
  • 74 Kjellen L, Lindahl U. Proteoglycans: structures and interactions.. Ann Rev Biochem 1991; 60: 443-75.
  • 75 Iozzo R. Proteoglycans: structure, function, and role in neoplasia.. Lab Invest 1985; 53: 373-96.
  • 76 Weitz JI. Low molecular weight heparins.. N Engl J Med 1997; 337: 688-98.
  • 77 Dawes J. Interactions of heparins in the vascular environment.. Haemostas 1993; 23 (Suppl. 01) 212-9.
  • 78 Nelson RM, Cecconi O, Roberts WG, Aruffo A, Lindhardt RJ, Bavilacqua MP. Heparin oligosaccharides bind L- and P-selectin and inhibit acute inflammation.. Blood 1993; 82: 3253-8.
  • 79 Cosmi B, Fredenburgh JC, Rischke J, Hirsh J, Young E, Weitz JI. Effect of nonspecific binding to plasma proteins on the antithrombin activities of unfractionated heparin, low molecular weight heparin, and dermatan sulfate.. Circ 1997; 95: 118-24.
  • 80 Rovelli G, Stone SR, Guidolin A, Sommer J, Monard D. Characterization of the heparin binding site of glia-derived nexin/protease nexin-1.. Biochem 1992; 31: 3542-9.
  • 81 Salzman E, Rosenberg RD, Smith MH, Lindon JN, Favreau L. Effect of heparin and heparin fragments on platelet aggregation.. J Clin Invest 1980; 65: 64-73.
  • 82 Kelton JG, Smith JW, Warkentin TE, Hayward CPM, Denomme GA, Horsewood P. Immunoglobulin G from patients with heparin-induced thrombocytopenia binds to a complex of heparin and platelet factor 4.. Blood 1994; 83: 3232-9.
  • 83 Lane DA, Denton J, Flynn AM, Thunberg L, Lindahl U. Anticoagulant activities of heparin oligosaccharides and their neutralization by platelet factor 4.. Biochem J 1984; 218: 725.
  • 84 Ross MA, Long WF, Williamson FB, Moffat CF. Effect of chemically modified heparins, and of heparin fragments, on Fe(II)-catalyzed peroxidation of linolenic acid.. Biochem Soc Trans 1992; 20: 2165.
  • 85 Blajchman MA, Young E, Ofosu FA. Effects of unfractionated heparin, dermatan sulfate and low molecular weight heparin on vessel wall permeability in rabbits.. Ann NY Acad Sci 1989; 556: 245-54.
  • 86 Kongsgaard UE, Aasen AO, Smith-Erichsen N, Bjornskau L. Effects of heparin on proteolytic activities in human plasma.. European Surg Res 1992; 24: 119-28.
  • 87 Muir JM, Hirsh J, Weitz JI, Andrew M, Young E, Shaughnessy SG. A histomorphometric comparison of the effects of heparin and low-molecular-weight heparin on cancellous bone in rats.. Blood 1997; 89: 3236-42.
  • 88 Vlodavsky I, Ishai-Michaeli R, Mohsen M, Bar-Shavit R, Catane R, Ekre HPT, Svahn CM. Modulation of neovascularization and metastasis by species of heparin.. Adv Exp Med Biol 1992; 313: 317-27.
  • 89 Myrmel T, Larsen TS, Reckerds O. Lipolytic effects of low molecular weight heparin (Fragmin) and heparin/dihydroergotamine in thromboprophylactic doses during total hip replacement.. Scand J Clin Lab Invest 1992; 52: 741-5.
  • 90 Schmitt Y, Schneider H. Low molecular weight heparin (LMWH): influence on blood lipids in patients on chronic haemodialysis.. Nephrol Dial Transplant 1993; 8: 438-42.
  • 91 Yanaka K, Spellman SR, McCarthy JB, Oegema TR, Low WC, Camarata PJ. Reduction of brain injury using heparin to inhibit leukocyte accumulation in a rat model of transient focal cerebral ischemia.. J Neurosurg 1996; 85: 1102-7.
  • 92 Shen ZX, Basara N, Xi XD, Caen J, Maffrand JP, Pascal M, Petiton M, Lormeau JC, Han ZC. Fraxiparin, a low-molecular-weight heparin, stimulates megakaryocytopoiesis in vitro and in vivo in mice.. Br J Haematol 1994; 88: 608-12.
  • 93 Norrby K, Ostergaard P. Basic fibroblast growth factor-mediated de-novo angiogenesis is more effectively suppressed by low molecular weight than by high molecular weight heparin.. Int J Microcirc Clin Exp 1996; 16: 8-15.
  • 94 Jayson GC, Gallagher JT. Heparin oligosaccharides: inhibitors of the biological activity of bFGF on Caco-2 cells.. Brit J Cancer 1997; 75: 9-16.
  • 95 Serra A, Esteve JC, Reverter JC, Lozano M, Escolar G, Ordinas A. Differential effect of a low-molecular-weight heparin (Dalteparin) and unfractionated heparin on platelet interaction with the subendothelium under flow conditions.. Thrombos Res 1997; 87: 405-10.
  • 96 Mikhailidis DP, Jagroop IA, Gantakis E, Knight CJ, Goodall AH. Low molecular weight heparin during instability in coronary artery disease.. Lancet 1996; 347: 1191.
  • 97 Lindahl U, Hook M. Glycosaminoglycans and their binding to biological macromolecules.. Assn Rev Biochem 1978; 47: 385-417.
  • 98 Regelson W. The growth-regulating activity of polyanions: a theoretical discussion of their place in the intercellular environment and their role in cell physiology.. In: Adv Cancer Res. Vol II Academic Press, Inc.; NY: 1968. pp. 223-304.
  • 99 Zimmerman J, Bar-Shavit R, Peretz T, Ben-Sasson SA. Control of cell proliferation by heparan sulfate and heparin-binding growth factors.. Thromb Haemost 1995; 74: 534-40.
  • 100 Buddecke E. Non-anticoagulant functions of heparin and heparan sulfate.. Hämostaseologie 1996; 16: 15-24.
  • 101 D’Amore PA. Heparin-endothelial cell interactions.. Haemostas 1990; 20 (Suppl. 01) 159-65.
  • 102 Yamazaki H, Oi H, Matsushita M, Inoue T, Tang JT, Nose T, Koizumi M, Tanaka E, Teshima T, Ozeki S, Nakamura H, Inoue T. Heparin induces rapid and remarkable elevation of hepatocyte growth factor/scatter factor during trans arterial embolization in renal cell carcinoma.. Anticancer Research 1997; 17: 1435-7.
  • 103 Engelberg H. Actions of heparin in the atherosclerotic process.. Pharmacol Rev 1996; 48: 327-52.
  • 104 Qabar A, Derick L, Lawler J, Dixit V. Thrombospondin 3 is a pentameric molecule held together by interchain disulfide linkage involving two cysteine residues.. J Biol Chem. 1995 270. 12,725-9.
  • 105 Abbate R, Gori AM, Modesti PA, Attanasio M, Martins F, Colella A, Giusti B, Cecioni I, Neri Serneri GG. Heparin, monocytes, and procoagulant activity.. Haemost 1990; 20 (Suppl. 01) 98-100.
  • 106 Au YPT, Kenagy RD, Clowes MM, Clowes AW. Mechanism of inhibition by heparin of vascular smooth muscle cell proliferation and migration.. Haemostas 1993; 23 (Suppl. 01) 177-82.
  • 107 Cerletti C, Rajtar G, Marchi E, De Gaetano G. Interaction between glycosaminoglycans, platelets, and leukocytes.. Sem Thrombos Hemostas 1994; 20: 245-53.
  • 108 Silvestro L, Viano I, Macario M, Colangelo D, Montrucchio G, Panico S, Fantozzi R. Effects of heparin and its desulfated drivatives on leukocyteendothelial adhesion.. Sem Thrombos Hemostas 1994; 20: 254-8.
  • 111 Luikart SD, Maniglia CA, Furcht LT, McCarthy JB, Oegema Jr. TR. A heparan sulfate-containing fraction of bone marrow stroma induces maturation of HL-60 cells in vitro.. Cancer Res 1990; 50: 3781-5.
  • 109 Manaster J, Chezar J, Shurtz-Swirski R, Shapiro G, Tendler Y, Kirstal B, Shasha SM, Sela S. Heparin induces apoptosis in human peripheral blood neutrophils.. Br J Haematol 1996; 94: 48-52.
  • 110 Granerus M, Engstrom W. Growth factors and apoptosis.. Cell Prolif 1996; 29: 309-14.
  • 112 Maeda S, Kimura H, Koga N, Lin KH, Saito T. Cell density-dependent DNA fragmentation and its suppression by heparin in primary culture of adult rat hepatocytes.. Biochem Biophys Res Comm 1993; 195: 270-5.
  • 113 Matzner Y, Marx G, Drexler R, Eldor A. The inhibitory effect of heparin and related glycosaminoglycans on neutrophil chemotaxis.. Thromb Haemost 1984; 52: 134-7.
  • 114 Bennett MR, Evan GI, Newby AC. Deregulated expression of the c-myc oncogene abolishes inhibition of proliferation of rat vascular smooth muscle cells by serum reduction, interferon-gamma, heparin, and cyclic nucleotide analogues and induces apoptosis.. Circ Res 1994; 74: 525-36.
  • 115 Wang A, Templeton DM. Inhibition of mitogenesis an c-fos induction in mesangial cells by heparin and heparan sulfates.. Kidney International 1996; 49: 437-48.
  • 116 Bianconi L, Martino AD, Orlandi V, Conaldi PG, Poniolo A, Camussi G. Development of inflammatory angiogenesis by local stimulation of Fas in vivo.. J Exp Med 1997; 186: 147-52.
  • 117 Cavari S, Ruggiero M, Vannucchi S. Antiproliferative effects of heparin on normal and transformed NIH/3T3 fibroblasts.. Cell Biol Int 1993; 17: 781-6.
  • 118 Maia RC, Wagner K, Cabral RH, Rumjanek VM. Heparin reverses rhoda-mine 123 extrusion by multidrug resistant cells.. Cancer Letts 1996; 106: 101-8.
  • 119 Meininger CJ. Mast cells and tumor-associated angiogenesis.. Chem Immunol 1995; 62: 239-57.
  • 120 Folkman J. Clinical applications of research on angiogenesis.. N Engl J Med 1995; 333: 1757-63.
  • 121 Iruela-Arispe M, Dvorak HF. Angiogenesis: a dynamic balance of stimulators and inhibitors.. Thromb Haemost 1997; 78: 672-7.
  • 122 Obermair A, Bancher-Todesca D, Bilgi S, Leodolter S, Gitsch G. Correlation of vascular endothelial growth factor expression and microvessel density in cervical intraepithelial neoplasia.. J Natl Cancer Inst 1997; 89: 1212-7.
  • 123 McCulloch P, Choy A, Martin L. Association between tumor angiogenesis and tumour cell shedding into effluent venous blood during breast cancer surgery.. Lancet 1995; 346: 1334-5.
  • 124 Weidner NW, Semple JP, Welch WR, Folkman J. Tumour angiogenesis and metastasis-correlation in invasive breast carcinoma.. N Engl J Med 1991; 324: 1-8.
  • 125 Horak E, Leek R, Klenk N, Lejeune S, Smith K, Stuart N, Greenall M, Stepniewska K, Harris AL. Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastasis and survival in breast cancer.. Lancet 1992; 340: 1120-4.
  • 126 Harris AL. Antiangiogenesis for cancer therapy.. Lancet 1997; 349 (Suppl. 11) 13-5.
  • 127 Folkman J, Langer R, Linhardt RJ, Haudenschild C, Taylor S. Angio-genesis inhibition and tumor regression caused by heparin or a heparin fragment in the presence of cortisone.. Science 1983; 221: 719-25.
  • 128 Jacobson AM, Hahnenberger R. Antiangiogenic effect of heparin and other sulphated glycosamino-glycans in the chick embryo chorioallantoic membrane.. Pharmacol Toxicol 1991; 69: 122-6.
  • 129 Derbyshire EJ, Comin GA, Yang YC, Overholser J, Watkins L, Thorpe PE. Anti-tumor and anti-angiogenic effects in mice of heparin conjugated to angiostatic steroids.. Internat J Cancer 1995; 63: 694-701.
  • 130 Ziche M, Ruggiero M, Pasquali F, Chiarugi VP. Effects of cortisone with and without heparin on angiogenesis induced by prostaglandin E1 and by S180 cells, and on growth of murine transplantable tumors.. Int J Cancer 1985; 35: 549-52.
  • 131 Thorpe PE, Derbyshire EJ, Andrade SP, Press N, Knowles PP, King S, Watson GJ, Yang Y-C, Rao-Bette M. Heparin-steroid conjugates: new angiogenesis inhibitors with antitumor activity in mice.. Cancer Res 1993; 53: 3000-7.
  • 132 Folkman J, Shing Y. Control of angiogenesis by heparin and other sulfated polysaccharides.. Adv Exper Med Biol 1992; 313: 355-64.
  • 133 Quyyumi AA, Diodati JG, Lakatos E, Bonow RO, Epstein SE. Angiogenic effects of low molecular weight heparin in patients with stable coronary artery disease: a pilot study.. J Amer Col Cardiol 1993; 22: 635-41.
  • 134 Pepe G, Guisti B, Attanasio M, Gori AM, Comeglio P, Martini F, Gensini G, Abbate R, Neri Serneri GG. Tissue factor and plasminogen activator inhibitor type 2 expression in human stimulated monocytes is inhibited by heparin.. Sem Thrombos Hemostas 1997; 23: 135-41.
  • 135 Wun TC. Lipoprotein-associated coagulation inhibitor (LACI) is a cofactor heparin: synergistic anticoagulant action between LACI and sulfated polysaccharides.. Blood 1992; 79: 430-8.
  • 136 Jeske W, Fareed J, Eschenfelder V, Iqbal O, Hoppensteadt D, Ahsan A. Biochemical and pharmacologic characteristics of reviparin, a low-molecular-mass heparin.. Sem Thrombos Hemostas 1997; 23: 119-28.
  • 137 Marsh NA, Minter AJ, Chesterman CN. The effect of heparin and other glycosaminoglycans on levels of tissue plasminogen activator and plasminogen activator inhibitor in cultured human umbilical vein endothelial cells.. Blood Coagul Fibrinol 1990; 1: 133-8.
  • 138 Kenagy RD, Clowes AW. Regulation of baboon arterial smooth muscle cell plasminogen activators by heparin and growth factors.. Thrombos Res 1995; 77: 55-61.
  • 139 Kohn S, Sakurama S, Morioka T, Ito Y, Yasukouchi T, Nakagawa S. The interaction between heparin and plasmin on amidolysis.. Thromb Haemost 1979; 42: 1261-75.
  • 140 Edelberg JM, Pizzo SV. Kinetic analysis of the effects of heparin and lipoproteins on tissue plasminogen activator mediated plasminogen activation.. Biochem 1990; 29: 5906-11.
  • 141 Takada Y, Urano T, Takada A. Effects of heparan sulfate analogue or other sulfated polysaccharides on the activation of plasminogen by t-PA or u-PA.. Thrombosis Res 1994; 73: 301-11.
  • 142 Edelberg JM, Weissler M, Pizzo SV. Kinetic analysis of the effects of glycosaminoglycans and lipoproteins on urokinase-mediated plasminogen activation.. Biochem J 1991; 276: 785-91.
  • 143 Alter SC, Kramps JA, Janoff A, Schwartz LB. Interactions of human mast cell tryptase with biological protease inhibitors.. Arch Biochem Biophys 1990; 276: 26-31.
  • 144 Ermolieff J, Boudier C, Laine A, Meyer B, Bieth JG. Heparin protects cathepsin G against inhibition by protein protease inhibitors.. J Biol Chem 1994; 269: 25,502-8.
  • 145 Evangelista V, Piccardoni P, Maugeri N, De Gaetano G, Cerletti C. Inhibition by heparin of platelet activation induced by neutrophil-derived cathepsin G.. Eur J Pharmacol 1992; 216: 401-5.
  • 146 Hornebeck W, Lafuma C, Robert L, Moczar RL, Moczar E. Heparin and its derivative modulate serine proteinases (SERPS) serine proteinase inhibitors (serpins) balance. Physiologic relevance.. Pathol Res Pract 1994; 190: 895-902.
  • 147 Wright SC, Wei QS, Zhong J, Zheng H, Kinder DH, Larrick JW. Purification of a 24-kD protease from apoptotic tumor cells that activates DNA fragmentation.. J Exp Med 1994; 180: 2113-23.
  • 148 Ermolieff J, Boudier C, Laine A, Meyer B, Bieth JG. Heparin protects Cathepsin G against inhibition by protein protease inhibitors.. J Biol Chem 1994; 269: 29502-8.
  • 149 Ying QL, Kemme M, Saunders D, Simon SR. Glycosaminoglycans regulate elastase inhibition by oxidized secretory leukoprotease inhibitor.. Am J Physiol 1997; 272: L533-41.
  • 150 Pratt CW, Tobin RB, Church FC. Interaction of heparin cofactor II with neutrophil elastase and cathepsin G.. J Biol Chem 1990; 265: 6092-7.
  • 151 Parker A, Gockerman A, Busby WH, Clemmons DR. Properties of an insulin-like growth factor-binding protein-4 protease that is secreted by smooth muscle cells.. Endocrinol 1995; 136: 2470-6.
  • 152 Hermans JM, Monard D, Jones R, Stone SR. Inhibition of acrosin by serpins. A suicide substrate mechanism.. Biochem 1995; 34: 3678-85.
  • 153 Hermans JM, Jones R, Stone SR. Rapid inhibition of the sperm protease acrosin by protein C inhibitor.. Biochem 1994; 33: 5440-4.
  • 154 Parish CR, Coombe DR, Jakobsen KB, Bennett FA, Underwood PA. Evidence that sulphated polysaccharides inhibit tumor metastasis by blocking tumor-cell-derived heparanases.. Int J Cancer 1987; 40: 511-8.
  • 155 Adachi T, Marklaund SL. Interactions between human extracellular super-oxide diamutase C and sulfated polysaccharides.. J Biol Chem 1989; 264: 8537-41.
  • 156 Kopitz J, Mukl C, Ehemann V, Lehmann C, Canty M. Effects of cell surface ganglioside sialidase inhibition on growth control and differentiation of human neuroblastoma cells.. Eur J Cell Biol 1997; 73: 1-9.
  • 157 Andera L, Mikulik K, Branny P, Puscheva MA. DNA-dependent RNA polymerase from an extremely thermophilic hydrogen-oxidizing bacterium Calderobacterium hydrogenophilum.. Biochem Biophys Res Comm 1991; 175: 949-54.
  • 158 DiCioccio RA, Srivastava BIS. Inhibition of deoxynucleotide-polymerizing enzyme activities of human cells and of simian sarcoma virus by heparin.. Cancer Res 1978; 38: 2401-7.
  • 159 Zacharski LR, Wojtukiewicz MZ, Costantini V, Ornstein DL, Memoli VA. Pathways of coagulation/fibrinolysis activation in malignancy.. Sem Thrombos Hemostas 1992; 18: 104-116.
  • 160 Fenton J. Thrombin and cancer.. In: New Anticoagulants for Cardiovascular Patient.. Piffare R. ed. Hanley and Belfus; Inc., Philadelphia,: 1997. pp 517-20.
  • 161 Schmitt M, Harbeck N, Thomssen C, Wilhelm O, Magdolen V, Reuning U, Ulm K, Hofler H, Janicke F, Graeff H. Clinical aspects of the plasminogen activation system in tumor invasion and metastasis: prognostic relevance and target for therapy.. Thromb Haemost 1997; 78: 285-96.
  • 162 van Meyer M, Smilde A, Tans G, Nesheim ME, Pannekoek H, Horrevoets AJG. The suicide substrate reaction between plasminogen activator inhibitor 1 and thrombin is regulated by the cofactors vitronectin and heparin.. Blood 1997; 90: 1874-82.
  • 163 Pratt CW, Church FC. Heparin binding to protein C inhibitor.. J Biol Chem 1992; 267: 8789-94.
  • 164 Jeske W, Fareed J. Antithrombin III- and heparin cofactor II-mediated anticoagulant and antiprotease actions of heparin and its synthetic analogues.. Sem Thrombos Hemostas 1993; 19 (Suppl. 01) 241-7.
  • 165 Petaja J, Fernandez JA, Gruber A, Griffin JH. Anticoagulant synergism of heparin and activated protein C in vitro.. J Clin Invest 1997; 99: 2655-63.
  • 166 Pepper MS, Vassalli JD, Wilks JW, Schweigerer L, Orei L, Montesano R. Modulation of bovine microvascular endothelial cell proteolytic properties by inhibitors of angiogenesis.. J Cell Biochem 1994; 55: 419-34.
  • 167 Espana F, Estelles A, Fernandez PJ, Gilabert J, Sanchez-Cuenca J, Griffin JH. Evidence for the regulation of urokinase and tissue type plasminogen activators by the serpin, protein C inhibitor, in semen and blood plasma.. Thromb Haemost 1993; 70: 989-94.
  • 168 Stetler-Stevenson WG, Hewitt R, Corcoran M. Matrix-metalloproteases and tumor invasion: from correlation and causality to the clinic.. Semin Cancer Biol 1996; 7: 147-54.
  • 169 Tyagi SC, Kumar S, Katwa L. Differential regulation of extracellular matrix metalloproteinase and tissue inhibitor by heparin and cholesterol in fibroblast cells.. J Mol Cell Cardiol 1997; 29: 391-404.
  • 170 Berghem LE, Ahlgren T, Grunfeldt MB, Lahnborg G, Schildt BE. Heparin-induced impairment of phagocytic and catabolic functions of the reticuloendothelial system in rats.. J Reticuloendothel Soc 1978; 23: 21-7.
  • 171 Bellavia A, Franklin V, Micklem HS. Effects of dextran sulphate and heparin on lymphocyte localization: lack of involvement of complement and other plasma proteolytic systems.. Int J Immunopharmacol 1980; 2: 311-20.
  • 172 Landborg G, Berghem L, Lagergren H, Schildt B. Effect of low-dose heparin on the phagocytic and catabolic function of the reticuloendothelial system in man during surgery.. Ann Chir Gynecol 1976; 65: 376-81.
  • 173 Rogers C, Welt FGP, Karnovsky MJ, Edelman ER. Monocyte recruitment and neointimal hyperplasia in rabbits: coupled inhibitory effects of heparin.. Arterioscler Thromb Vasc Biol 1996; 16: 1312-8.
  • 174 Balow JE, Fauci AS. Heparin and lymphocyte kinetics: use in studies on the mechanisms of corticosteroid-induced peripheral lymphocytopenia.. J Reticuloendothel Soc 1976; 19: 221-6.
  • 175 Shiu W, Schor S. Quantitative study of various factors influencing the migration of lymphocytes in vitro: glucocortico-steroid, PHA, cyclosporine A, and heparin.. Cell Biol Int Rep 1987; 11: 171-80.
  • 176 Lider O, Mekori YA, Miller T, Bar-Tana R, Vlodavsky I, Baharav E, Cohen IR, Naparstik Y. Inhibition of T lymphocyte heparanase by heparin prevents T cell migration and T cell-mediated immunity.. Eur J Immunol 1990; 20: 493-9.
  • 177 Thurn AL, Underhill CB. Heparin-induced aggregation of lymphoid cells.. J Cell Physiol 1986; 126: 352-8.
  • 178 Dziarski R. Enhancement of mixed leukocyte reaction and cytotoxic anti-tumor responses by heparin.. J Immunol 1989; 143: 356-65.
  • 179 Sugawara I, Ishizaka S. Polysaccharides with sulfate groups are human T-cell mitogens and murine polyclonal B-cell activators (PBAs).. Cellular Immunol 1982; 74: 162-71.
  • 180 Eskinazi DP, Perna JJ, Ershow AG, Sharrow SO. Effects of heparin on in vivo immune parameters.. J Biol Response Mod 1988; 7: 173-84.
  • 181 Gorski A, Wasik M, Stepien-Sopniewska B, Glapinski T. Heparin and platelet interactions influence alloantigen-induced proliferative responses of human T lymphocytes and immunoglobulin synthesis in vivo.. Immunol Letts 1991; 28: 161-6.
  • 182 Lider O, Baharav E, Mekori YA, Miller T, Naparstels Y, Vlodavsky I, Cohen IR. Suppression of experimental autoimmune diseases and prolongation of allograft survival by treatment of animals with low doses of heparin.. J Clin Invest 1989; 83: 752-6.
  • 183 Yamamoto H, Fuyama S, Arai S, Sendo F. Inhibition of mouse natural killer cell cytotoxicity by heparin.. Cell Immunol 1985; 96: 409-17.
  • 184 Gorelik E. Augmentation of the antimetastatic effect of anticoagulant drugs by immunostimulation in mice.. Cancer Res 1987; 47: 809-15.
  • 185 Ames BN. Endogenous oxidative DNA damage, aging, and cancer.. Free Rad Res Comm 1989; 7: 128-8.
  • 186 Cerutti PA. Oxy-radicals and cancer.. Lancet 1994; 344: 862-3.
  • 187 Stevens RG, Graubard BI, Micozzi MS, Neriishi K, Blumberg BS. Moderate elevation of body iron level and increased risk of cancer occurrence and death.. Int J Cancer 1994; 56: 364-9.
  • 188 Stevens RG. Iron and cancer.. In: Iron and Human Disease.. Lauffer RB. ed. CRC Press; Boca Raton, FL: 1992. pp 334-47.
  • 189 Hiebert LM, Lui J. Heparin protects cultured arterial endothelial cells from damage by toxic oxygen metabolites.. Atherosclerosis 1990; 83: 47-51.
  • 190 Hladovec J. Protective effect of oxygen-derived free radical scavengers on the endothelium in vivo.. Physiol Bohemoslov 1986; 35: 97-103.
  • 191 Chaubel KA, Godbole CS. Radiobiological effect of heparin in Swiss mice, human amnion cells and E. coli B/r irradiated with Co60 gamma-rays.. Radiat Environ Biophys 1983; 22: 281-6.
  • 192 Bazzoni G, Nunez AB, Mascellani G, Bianchini P, Dejana E, Del Maschio A. Effect of heparin, dermatan sulfate, and related oligo-derivatives on human polymorphonuclear leukocyte functions.. J Lab Clin Med 1993; 121: 268-75.
  • 193 Albertini R, Rindi S, Passi A, Palladini G, Pallavicini G, DeLuca G. The effect of heparin on Cu2+-mediated oxidation of human low-density lipoproteins.. FEBS Letts 1995; 377: 240-2.
  • 194 Metcalf DD, Thompson HL, Klebanoff SJ, Henderson Jr. WR. Oxidative degradation of rat mast-cell heparin proteoglycan.. Biochem J 1990; 272: 51-7.
  • 195 Albertini R, Rindi S, Passi A, Palavicini G, DeLuca G. Heparin protection against Fe2+- and Cu2+-mediated oxidation of liposomes.. FEBS Letts 1996; 383: 155-8.
  • 196 Flick MR, Hoeffel JM, Staub NC. Superoxide dismutase with heparin prevents increased lung vascular permeability during air emboli in sheep.. J Appl Physiol Resp Environ Exercise Physiol 1983; 55: 1284-91.
  • 197 Lapenna D, Mezzetti A, De Gioia S, Ciofani G, Marzio L, Di Ilio C, Cuccurullo F. Heparin: does it act as an antioxidant in vivo?. Biochem Pharmacol 1992; 44: 188-91.
  • 198 Toivonen HJ, Akotupa M. Free radical reaction products and antioxidant capacity in arterial plasma during coronary artery bypass grafting.. J Thorac Cardiovasc Surg 1994; 108: 140-7.
  • 199 Paulikova H, Petrickova I, Antalik M, Podhradsky D. Effect of heparin and dextran sulfate on the activity of glutathione reductase from yeast.. Biochem Mol Biol Int 1996; 38: 1117-26.
  • 200 Wu HF, Lundblad RL, Church FC. Neutralization of heparin activity by neutrophil lactoferrin.. Blood 1995; 85: 421-8.
  • 201 Regoeczi E, Chindemi PA, Hu WL. Interaction of transferrin and its iron-binding fragments with heparin.. Biochem J 1994; 299: 819-23.
  • 202 Bailar JC III. The promise and problems of meta-analysis.. N Engl J Med 1997; 337: 559-61.
  • 203 Turpie AG. New frontiers in the management of unstable coronary artery disease.. Am J Cardiol 1997; 80: 21E-24E.